Management of HIV disease involves combination regimens of antiretroviral drugs including the protease inhibitors. Pharmacologically these compounds are of interest and a number of questions remain as to how best assure their optimal use. Pharmacokinetically, the protease inhibitors are prone to drug interactions as these drugs are complex metabolically being primarily metabolized by cytochrome P450 isozymes. In addition, issues relation to overall drug exposure and how this correlates with clinical outcome (pharmacodynamics) is of importance as suboptimum exposure (e.g. low drug levels and/or poor adherence) can result in the development of drug resistance while excessive exposure (e.g. high drug levels) may lead to toxicity. Both pharmacokinetic changes as well as variability in adherence to prescribed regimens (two separate components) can impact on exposure of these drugs and their insulting clinical effect. Ethanol is a substance of abuse for HIV infected patients and it may alter the pharmacokinetics of these drugs either by inducing drug metabolism as observed in the present of acutely high ethanol levels. This project will investigate these potential ethanol effects and determine the pharmacokinetics and pharmacodynamics of these antivirals in chronic ethanol users as compared to light/non-drinkers. The pharmacokinetic component of this project will include pharmacokinetic evaluations of the protease inhibitors in chronic ethanol users during acute co- administration with ethanol, as well as in the absence of acutely high levels of ethanol, to investigate the potential metabolic inhibiting and inducing effects of ethanol respectively. The data will be compared to results obtained in light/nondrinkers, using both population pharmacokinetic measurements as well as information on adherence so that overall drug exposure can be estimated. This in turn will be correlated in the Program Project with measures of clinical response (relating to the CNS and PNS morbidity of HIV disease). Finally, the disposition of these drugs in the CSF will be investigated. This project will provide important data on the effect of chronic heavy ethanol use on the metabolism and efficacy of anti-retroviral agents for HIV disease.